This invention relates to medicaments, particularly a pharmaceutical composition for periodontitis treatment as periodontal tissue local injection, which comprises a bisphosphonic acid derivative or a salt thereof as an active ingredient.
Periodontitis is a disease in which chronic gingivitis progresses and inflammation is also spread to periodontal tissues other than gingiva, which accompanies progressive destruction of periodontal tissues. Clinically, chronic inflammation of gingiva, bleeding from periodontal pockets, alveolar bone resorption and the like are observed, and it is known that mobility and movement of teeth occur as the destruction advances, finally causing spontaneous loss of a tooth or a necessity of tooth extraction. The treatment of periodontitis includes removal of dental plaque and dental calculus as causal substances, and removal of degenerative, necrosed tissues by root planing and periodontal surgery and the like for the purpose of effecting reattachment of gingiva (Periodontal Therapy (2nd edition), pp. 215-226 (1992), published by Ishiyaku Shuppan). In the drug therapy of periodontitis, tetracycline antibiotics are mainly used with the aim of removing periodontitis-associated bacteria. However, a drug that directly acts upon alveolar bone resorption, which is an important clinical manifestation of periodontitis, does not exist to date, so that a drug having such an action is expected to have usefulness as a novel therapeutic agent for periodontitis.
Bisphosphonate (hereinafter, BP) is a structural analog of pyrophosphoric acid, which is stable in the living body, and has biological actions such as heterotopic calcification inhibitory action, bone resorption inhibitory action and the like. BP has already been used in the clinical field as a therapeutic agent for hypercalcemia accompanied by a malignant tumor, Paget""s disease, osteoporosis and the like, and its action on alveolar bone resorption caused by periodontitis is also expected due to its pharmacological actions. An action of BP to inhibit periodontal tissue destruction in rats has been reported (J. Dent. Res., 11, 1430-1433 (1988)), and it has been reported in recent years that alendronate, which is a second generation BP, inhibited alveolar bone destruction in monkey and dog periodontitis models by its oral administration (J. Periodontol., 63, 825-830 (1992), J. Periodontol., 66(3), 211-217 (1995)). Also, it has already been reported that incadronate disodium (chemical name disodium cycloheptylaminomethylenediphosphonate monohydrate; to be referred to as incadronate hereinafter) is a third generation BP having potent bone resorption inhibitory action (Japanese Patent Publication No. 629/1995) and exerts alveolar bone loss inhibitory action in a hamster periodontitis model (Dentistry Basic Medicine Journal, 36(5), 510-519 (1994)) and alveolar bone loss inhibitory and attachment level improving actions in a canine periodontitis model, by its subcutaneous or oral administration respectively (J. Periodont. Res., 33, 196-204 (1998)).
In such oral administration, subcutaneous injection, intravenous injection and the like systemic administrations, it is considered that bone resorption inhibitory action is exerted by the transfer of drug effect-inducing amount of BP into an affected part of the alveolar bone, and there is a possibility that BP is simultaneously transferred into other tissues in the same manner, and express bone resorption inhibitory action particularly in systemic bone tissues in the same manner, thus inducing undesirable actions.
On the other hand, attempts have been made to administer BP topically; for example, it has been reported that topical administration of risedronate to the sub-periosteum area adjacent to the first molar and topical administration of pamidronate to sub-mucasa on palate-side are effective in rat molar experimental tooth movement models (J. Dent. Res., 73(8), 1478-1484 (1994); Orthod. Waves, 57(5), 307-317 (1998)).
However, there are no reports to date on alveolar bone resorption inhibitors for use in the topical administration of BP, which are clinically usable in human. Actually, since there are differences in the shape, size, stimulation property and the like of periodontal tissues between rats and human, it is difficult to predict suitable topical administration concentration, dose, administration method and the like at human periodontal tissues or their periphery from the above information in rats.
WO 93/11774 discloses a periodontitis-treating agent of alendronate, but its main administration method is a systemic administration by oral administration or intravenous injection. Regarding its topical administration, it is described that it can be directly applied to inflammatory parts of teeth and gingiva, but there are no illustrative disclosures on its dose, administration site and the like, merely suggesting a possibility. What is more, in this method for directly applying it to inflammatory parts of teeth and gingiva, not only transfer rate of BP into alveolar bone is low but also a possibility of orally systemic administration with saliva is suggested, so that its alveolar bone-selective administration cannot be expected at all.
In addition, there are reports stating that a BP having amino group has a local irritative property (Lancet, 348, No. 9023, 345-346 (1996); Br. Med. J., 295, No. 6609, 1301-1305 (1987)), that is, it is completely unclear whether or not the treatment of periodontitis by topical administration of BP to periodontal tissues or adjacent tissues thereof in human is actually possible.
Great concern has been directed toward the creation of a topical administration medicament useful as a periodontitis treating agent containing BP as the active ingredient, which has an alveolar bone-selective bone resorption inhibitory action, is convenient as the administration method and has high practical values clinically in human.
The present inventors have carried out examinations on the periodontitis treating agents for topical administration using a canine periodontitis model having periodontal tissues bearing resemblance to those of human, making use of incadronate whose periodontitis treating action had been confirmed by oral administration, and found unexpectedly that BP can be transferred alveolar bone-selectively and good alveolar bone resorption inhibitory action and periodontitis treating action can be expressed, when BP is topically injected using an alveolar mucosa injection method conventionally used as a method for injecting anesthetic drugs in the field of dentistry, thereby accomplishing the invention. What is more, this administration method was a topical administration method, which is easy to handle, has less burden to patients and has clinically high practical value.
Accordingly, the invention relates to a pharmaceutical composition for treating human periodontitis, which comprises a bisphosphonic acid derivative or a salt thereof and a pharmaceutically acceptable carrier, characterized in that it is for topical injection by an alveolar mucosa injection method. The injecting volume of the pharmaceutical composition of the invention for topical injection by an alveolar mucosa injection method is preferably from 100 to 300 xcexcl per one administrating site. Also, a pharmaceutical composition in which the bisphosphonic acid derivative or a salt thereof is incadronic acid or a salt thereof is desirable, and a pharmaceutical composition in which concentration of incadronic acid or a salt thereof is from 3.33 to 100 xcexcg/ml is more desirable. Dose of incadronic acid or a salt thereof is preferable from 0.5 xcexcg to 15 xcexcg per one administrating site.
In addition, according to the inventors"" studies, canine periodontal tissues were apt to undergo influence of local irritation by BP, and good therapeutic effects could not be obtained due to the local irritation at a concentration of topical dose capable of achieving an alveolar bone concentration similar to the alveolar bone concentration at the time of systemic administration, so that it was considered that topical administration of a periodontitis treating agent containing BP to periodontal tissues in human, whose periodontal tissues are similar to those of canines, will be difficult due to this local irritation.
However, when the inventors have carried out further examinations, it was found unexpectedly that good alveolar bone resorption inhibitory action can be expressed by topically injecting incadronate into periodontal tissues in an amount far smaller than the dose predicted from the alveolar bone concentration at the time of systemic administration.
Accordingly, another embodiment of the invention is a pharmaceutical composition for treating periodontitis as a composition for human periodontal tissue topical injection, which comprises a bisphosphonic acid derivative or a salt thereof in an amount small enough so that local irritation to human periodontal tissues as the administration site can be accepted but the amount sufficient for exerting alveolar bone resorption inhibitory action by topical injection, illustratively, from 3.33 to 100 xcexcg/ml of incadronic acid or a salt thereof and a pharmaceutically acceptable carrier.
In addition, the invention also relates to a dental cartridge that comprises the pharmaceutical composition of the invention.
Also preferred as other embodiments of the invention are a method for treating patients with periodontitis, characterized in that an effective amount of a bisphosphonic acid derivative or a salt thereof is administered by an alveolar mucosa injection method, a method for treating patients with periodontitis, characterized in that an injection comprising incadronic acid or a salt thereof in a concentration of from 3.33 to 100 xcexcg/ml is topically administered to periodontal tissues of the patient in a volume of from 100 to 300 xcexcl per one administration site, and use of a bisphosphonic acid derivative or a salt thereof for the manufacture of an agent for inhibiting alveolar bone resorption and for use in topical injection by an alveolar mucosa injection method.
The following describes the invention in detail.
The term xe2x80x9cbisphosphonic acid derivative or a salt thereofxe2x80x9d as used herein means a compound or a salt thereof which is characterized in that it is a structural analog to pyrophosphoric acid stable in the living body, has two phosphonic acid residues and has a bone resorption inhibitory action. Examples of the bisphosphonic acid derivatives already known as bone resorption inhibitors include clodronate, tiludronate, neridronate, pamidronate, incadronate, alendronate, olpadronate, EB-1053, risedronate, ibandronate, zoledronate, YM529 (1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-bisphosphonic acid) and salts thereof. Preferred are incadronate, alendronate, olpadronate, EB-1053, risedronate, ibandronate, zoledronate and YM529, and particularly preferred is incadronate.
The xe2x80x9cincadronic acid or a salt thereofxe2x80x9d of the invention is a compound selected from incadronic acid and pharmaceutically acceptable salts thereof including incadronate (incadronate disodium). Hydrates, solvates and polymorphic substances thereof are also included therein. Preferred is incadronate.
The inventors studied practical administration methods that can transfer BP alveolar bone-selectively using incadronate. Administration methods generally employed for periodontitis treating agents, such as attachment and adhesion to gingiva, and administration into periodontal pockets, are poor in practical values because of the low transfer late of BP to alveolar bone and a possibility of causing gingival irritation. Furthermore the administration into periodontal pockets has further low transfer late due to a distance from the alveolar bone and has a possibility of causing leaking of a drug from the pockets into the mouth.
The inventors have found that topical injection into periodontal tissues around alveolar bone, namely into gingiva, alveolar mucosa, sublingual mucosa, palate part and the like, is most desirable as a method for transferring a drug to the alveolar bone. However, since the periodontal tissue around the alveolar bone where topical injection of a drug can be actually carried out is very small, the volume that can be administered is limited, and there is a possibility of causing patients a pain, so that further improvement of the administration method is desired.
Thus, the inventors have found that the use of an alveolar mucosa injection method which had not been used in the field of dentistry other than the infiltration anesthesia renders possible easy topical injection of a BP-containing periodontitis treating agent in a volume of from 100 to 300 xcexcl per one site around the alveolar bone, and it also renders possible alveolar bone-selective transfer of effective amount of BP as will be described later so that good alveolar bone resorption inhibitory effect or periodontitis treating effect can be obtained by simple handling and with less burden to patients. That is, it was found for the first time in the world that the alveolar mucosa injection method is a method having high practical values for topically administrating a BP-containing periodontitis treating agent into human periodontal tissues.
The term xe2x80x9calveolar mucosa injection methodxe2x80x9d as used herein means a method in which a drug solution is injected between periosteum of the alveolar bone and alveolar mucosa by inserting a needle not vertically but in a laying position into a flexible oral mucosa region adjacent to gingiva (the alveolar mucosa shown in FIG. 1, or sublingual mucosa), preferably around a border with gingiva. Illustratively, a drug solution is injected by laying a needle into the alveolar mucosa shown in FIG. 1, preferably around the mucogingival junction when the injection is carried out on the buccal side of teeth, and into the sublingual mucosa, preferably a region close to the jaw bone, on the lingual side. Regarding the angle for inserting a needle, close to horizontal within a possible range is advantageous, because it hardly gives a pain to patients and the drug solution can be easily injected. Preferably, it may be inserted at a laying angle of 10 degrees or less based on the mucosa region. However, since the palate side of the upper jaw has no alveolar mucosa or a flexible mucosa analogous thereto, a drug is injected by inserting a needle into a region about 1 cm-distant from the tooth jaw region, and this method is also included in the invention as an embodiment of the alveolar mucosa injection method.
This alveolar mucosa injection method is also called a horizontal method or a sub-mucous injection method, which is a known injection method conventionally used as one of the infiltration anesthesia methods used in the field of dentistry. Since an anesthetic drug is injected not into gingiva but under a flexible alveolar mucosa such as a region between gingiva and cheek, this method is markedly simple, requires a short period of time and causes pain only at the first insertion, so that it is known as a method having less burden on the dentists in charge and patients (Periodontal Therapy (2nd edition), pp. 325-326 (1992), published by Ishiyaku Shuppan). The injection method called alveolar mucosa injection method, horizontal method or sub-mucous injection method conventionally used as one of the infiltration anesthesia methods is a preferred embodiment of the xe2x80x9calveolar mucosa injection methodxe2x80x9d of the invention.
Since desirable handling method of the alveolar mucosa injection method is disclosed in Periodontal Therapy (2nd edition), pp. 325-326 (1992), published by Ishiyaku Shuppan, its description is extracted in the following though the alveolar mucosa injection method of the invention is not restricted by this description.
xe2x80x9cIn carrying out, the vestibule of mouth is firstly exposed by pressing a lip or cheek with a finger or dental mirror, and a needle is inserted into a flexible mucosa having loose connective tissue (alveolar mucosa) only a few mm by laying it not vertically but horizontally. Thereafter, when a blister is formed under the mucosa by gradually starting release of the liquid and then the release is further continued toward distal side by laying the needle as such, a bank-like swelling is formed. (Omission) On the lingual side, similar swelling is formed by inserting it into a region of the sublingual mucosa close to the jaw bone. In this connection, since the palate side of the upper jaw does not have a flexible mucosa, usual infiltration anesthesia is carried out at 1 cm intervals on a region about 1 cm-distant from the tooth jaw.xe2x80x9d
The inventors have confirmed previously that oral administration of incadronate shows an alveolar bone resorption inhibitory action dose-dependently in a canine periodontitis model, and found that its suitable dose is 1.0 mg/kg (J. Periodont. Res., 33, 196-204 (1998)). Thereafter, it was confirmed that the drug concentration in the alveolar bone is about 4 xcexcg/g in that case.
It was found also that, by 10 or 100 xcexcg/50 xcexcl/kg (200 or 2,000 xcexcg/ml drug concentration) of incadronate intra-gingival (substantially around gingiva) administration in a tooth movement model in rat, no effect is observed in the 10 xcexcg/50 xcexcl/kg group (average concentration in the alveolar bone: 0.6 xcexcg/g), good tooth relapse inhibitory action is observed in the 100 xcexcg/50 xcexcl/kg group (average concentration in the alveolar bone: 14 xcexcl/g), and local irritation is not observed in gross observation.
Contrary to the above knowledge, however, in a study using a canine model having periodontal tissues analogous to those of human, as will be shown later in the study example, it was unable to exert alveolar bone resorption inhibitory action by a periodontal tissue topical injection of 50 xcexcg or 150 xcexcl/150 xcexcl/site (site: per one administration site; 333 or 1,000 xcexcl/ml drug concentration) which gives an intra-alveolar bone drug concentration similar to the case of oral administration. What is more, a considerable local irritation was observed in the 150 xcexcg/150 xcexcl/site group, and it was considered that this was originated from the local irritative effect of incadronate. Actually, since the periodontal tissue is very small so that the injectable volume of a drug is limited, it was considered that it is difficult to achieve the above effective intra-alveolar bone drug concentration by an injection of a low drug concentration without local irritation.
The inventors have conducted intensive studies and unexpectedly found as a result that good alveolar bone resorption inhibitory action can be exerted when incadronate is topically injected by the alveolar mucosa injection method at a dose far smaller than the amount that can achieve the aforementioned intra-alveolar bone concentration at the time of oral administration. That is, it was found that a BP concentration having both of clinically acceptable low local irritative property and sufficient alveolar bone resorption inhibitory action is present (from 0.5 to 15 xcexcg/150 xcexcl in the case of incadronate, namely from 3.33 to 100 xcexcg/ml as the drug concentration). This optimum BP concentration can be found also on other BPs than incadronate by confirming local irritation and alveolar bone resorption inhibitory action through topical BP injection studies, preferably topical injection studies by the alveolar mucosa injection method, using an animal model of a canine, monkey or the like having periodontal tissues analogous to those of human. In this regard, administration frequency and administration interval are concerned in the expression of local irritation property so that they should be taken into consideration optionally.
In the case of incadronate as one of the preferred embodiments of the invention, a drug concentration of from 3.33 to 100 xcexcg/ml, more preferably from 10 to 80 xcexcg/ml, most preferably from 25 to 75 xcexcl/ml, is the optimum concentration having a clinically acceptable low local irritative property and sufficient alveolar bone resorption inhibitory action by topical injection, and incadronate of this concentration can be topically injected at a volume of from 100 to 300 xcexcl, preferably from 150 to 200 xcexcl, per one administration site. It is desirable that the administration is carried out to either the buccal side or lingual side, preferably both sides (two sites), per one tooth to be treated. This is administered once, or 2 to 10 times at intervals of 1 day to several weeks. Preferably, it is desirable to carry out the administration 2 to 10 times at intervals of 3 days to 14 days. More preferable dosage schedule should be optionally selected in response to the drug concentration, and it is desirable to narrow the administration intervals and increase the frequency in the case of a low concentration or to prolong the administration intervals and reduce the frequency in the case of a high concentration. For example, it is desirable to carry out the administration 3 to 9 times at one week intervals when 1.5 xcexcg/150 xcexcl-200 xcexcl/site is administered to two sites per one tooth to be treated, 3 to 6 times at one week intervals when 5 xcexcl/150 xcexcl-200 xcexcl/site is administered to two sites per one tooth to be treated, or 2 to 3 times at two week intervals when 15 xcexcg/150 xcexcl-200 xcexcl/site is administered to two sites per one tooth to be treated.
The aforementioned alveolar mucosa injection method is suitable as the topical injection method, but even in the case of the use of other periodontal tissue injection methods such as an inter-dental papilla injection method, the efficacy at these concentrations can be expressed with the proviso that the method can perform injection at a volume of from 100 to 300 xcexcl per one administration site. Accordingly, these injection methods are also included in the topical injection of the invention.
The alveolar bone resorption inhibitor for topical injection of the invention contains aseptic aqueous or non-aqueous solutions, suspending agents and emulsifying agents. Examples of the aqueous solutions include distilled water for injection and physiological saline. Examples of the non-aqueous solutions include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol and Polysorbate 80 and the like. Such compositions may further contain auxiliary agents such as an antiseptic agent, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, a solubilization-assisting agent and an isotonicity agent (e.g., xylitol, mannitol, sorbitol or ethylene glycol). They may be sterilized by filtration through a bacteria-retaining filter, blending of a germicide or irradiation, or produced under an aseptic condition. They can also be used by firstly producing aseptic solid compositions and then dissolving in sterile water or a sterile solvent for injection prior to use. From the viewpoint of clinical use, it is desirable to provide the alveolar bone resorption inhibitor of the invention particularly as a dental cartridge.